Genetic toxicology encompasses the study of the interactions of chemical and physical agents with the process of heredity. In this field, there is a considerable amount of interest in the identification of structural genetic lesions and their possible genetic consequence(s). In view of the heritable nature of the cancer cell's phenotype it is reasonable to, at the present time, assume that DNA damage is involved in the mechanism of chemical carcinogenesis. Based in part on an analogy to mutagenesis studies it is sometimes assumed that initiation of carcinogenesis can be described as a random "hit" phenomenon. This concept of initiation as a random mutational event has been extended to suggest a random interaction of carcinogens with DNA. The possible role of non-random gene damage in genetic toxicology, particularly potential alterations in sites of damage during the initiation stage of chemical carcinogenesis, is a potentially fruitful area of research which has not been adequately explored. This research project is addressed to this question. The working hypothesis behind the proposal is the following: The damage which occurs to the DNA of target tissue is distributed in a non-random fashion within the genome followig exposure to chemical carcinogens. The possible biological consequences of non-random DNA damage/repair are viewed within the context of the two-stage theory of carcinogenesis, i.e., initiation followed by promotion. This proposed research project is addressed towards an assessment, in vivo, of aspects of chemical carcinogen-induced DNA damage/ repair in specific chromatin fractions isolated from precancerous liver. The carcinogens to be employed for these studies will be 2-acetylaminofluorene and alkylating agents. I plan to address the question of whether or not DNA damage and/or repair occurs in a non-random fashion within the genome of selected populations of hepatic cells, and ascertain if there are changes in the regions of the genome subject to DNA damage/repair, during the early phases of hepatocarcinogenesis. The presence of specific adducts, as well as total carcinogen binding, will be monitored. DNA damage will also be assessed by determining single strand breaks in DNA and by measuring the capacity of purified DNA to serve as a template for RNA synthesis. The overall objective of the project is to discern initial molecular events in the carcinogenic process. In addition, the results of these proposed studies might aid in the development of experimental biological models for use in preliminary screening procedures for the detection of environmental carcinogens.